Journal UPJO

Int. J. Exp. Path.
(2011), 92, 168192
REVIEW ARTICLE
Congenital ureteropelvic junction obstruction: human disease and

animal models
Julie Klein*, Julien Gonzalez*, Mathieu Miravete*, Cecile Caubet*, Rana Chaaya*,
Stephane Decramer*, Flavio Bandin, Jean-Loup Bascands*, Benedicte Buffin-Meyer* and
Joost P. Schanstra*
*Institut National de la Sante et de la Recherche Medicale (INSERM), Toulouse, France, Universite Toulouse III Paul-Sabatier,
Institut de Medecine Moleculaire de Rangueil, Toulouse, France and Department of Pediatric Nephrology, Hopital des Enfants,
Centre de Reference du Sud Ouest des Maladies Renales Rares, Toulouse, France
INTERNATIONAL Summary
JOURNAL OF Ureteropelvic junction (UPJ) obstruction is the most frequently observed cause of
EXPERIMENTAL obstructive nephropathy in children. Neonatal and foetal animal models have been
developed that mimic closely what is observed in human disease. The purpose of this
PATHOLOGY
review is to discuss how obstructive nephropathy alters kidney histology and func-
tion and describe the molecular mechanisms involved in the progression of the
lesions, including inflammation, proliferation apoptosis, reninangiotensin system
doi: 10.1111/j.1365-2613.2010.00727.x
activation and fibrosis, based on both human and animal data. Also we propose that
Received for publication: 7 April 2010 during obstructive nephropathy, hydrodynamic modifications are early inducers of
Accepted for publication: 3 June 2010 the tubular lesions, which are potentially at the origin of the pathology. Finally, an
Correspondence: important observation in animal models is that relief of obstruction during kidney
Benedicte Buffin-Meyer development has important effects on renal function later in adult life. A major
Institut National de la Sante et de la short-coming is the absence of data on the impact of UPJ obstruction on long-term
Recherche Medicale (INSERM), U858
Toulouse adult renal function to elucidate whether these animal data are also valid in humans.
France
E-mail: benedicte.buffin- Keywords
meyer@inserm.fr fibrosis, mechanical stress, neonatal models
obstruction is efficient in protecting against short term

Introduction
detectable renal lesions, increasing support obtained in both
Congenital obstructive nephropathy is the main cause of end experimental- and human-studies is available suggesting that
stage renal disease (ESRD) in children (Benfield et al. 2003). UPJ obstruction induces permanent modifications of the
This contrasts sharply with adult ESRD which for the renal parenchyma.
greater part originates from ageing and type II diabetes. Other causes of congenital obstructive nephropathy
Hydronephrosis, defined clinically by an enlargement of the include disorders of the urethra such as posterior valves or
kidney as a result of urine accumulation in the renal pelvis disorders of the bladder such as trigonal cysts (Roth et al.
or calyces, is a consequence of obstructive nephropathy. The 2002). However, these are all rare diseases. Therefore, we
most frequently found cause of hydronephrosis is uretero- will focus in this review on unilateral UPJ obstruction as it
pelvic junction (UPJ) obstruction with an estimated inci- is the most frequently encountered obstructive nephropathy
dence of 1 in 10001500 (Chang et al. 2004). UPJ in children and therefore the majority of the insight of
obstruction is mostly considered as a functional obstruction human obstructive nephropathy comes from this pathology.
originating from abnormalities in the smooth muscle of the In addition, excellent neonatal rodent and foetal models for
pelvis and ureter (Mendelsohn 2004). Physical obstruction partial and complete UPJ obstruction have been developed
of the ureter, e.g. compression of the UPJ by crossing ves- (Peters 2001; Thornbill et al. 2005). We have attempted to
sels, is also observed but whether the vessel alone causes combine all the available knowledge obtained in human UPJ
obstruction or whether there is also a functional component obstruction, animal models and in vitro studies with the pur-
is still debated (Yiee et al. 2010). Although surgery in UPJ pose of identifying concepts that hold both in the models
168 2010 The Authors. Journal compilation 2010 Blackwell Publishing Ltd
Congenital UPJ obstruction 169
and in human pathology and to support future experiments more rationally. However, the often observed infertility or
aiming at the better understanding of obstructive nephropa- low reproduction status of these strains limits the use of
thy and drug testing. such models (Peters 2001).
As the response of the adult kidney to obstruction clearly Unilateral ureteral obstruction (UUO) is a well-known
differs from the response of the foetal kidney (Chevalier surgical model to study tubulointerstitial fibrosis in adult
et al. 2009), all work described in this review concerns rodents (Bascands & Schanstra 2005). However, the effects
responses to foetal or neonatal obstruction. Any reference to of obstruction in the mature adult kidney differ widely of
adult obstruction is clearly indicated and foetal neonatal what happens in the developing kidney. Indeed, in the latter,
obstruction is the default situation. the obstruction can interfere with kidney morphogenesis,
growth and maturation. For this reason, different models of
prenatal obstruction have been developed in many species
Causes UPJ obstruction (Peters 1997). Compared to the congenital models, they
offer the advantages of controlling the onset, the duration
Causes of human UPJ obstruction
and the severity of the pathology. In sheep, primate and gui-
Effective urine transport depends on formation of proper nea pig, in which renal nephrogenesis, like in humans, is
connections and functioning between the kidney and the ure- completed before birth but where renal maturation contin-
ter. In UPJ obstruction attention has been drawn on the ues after birth, UUO must be performed during foetal life
development of smooth muscle cells that line the pelvis and (Chevalier et al. 2009). However intrauterine surgery is a
the ureter and conduct peristaltic waves to expel urine complex procedure. An alternative to this approach is the
(Chang et al. 2004; Lye et al. 2010). Failure in development use of the opossum, which is a marsupial with extrauterine
of the renal pelvis or impaired smooth muscle differentiation foetal development. The surgery can thus be performed in
can, indeed, lead to functional obstruction and hydronephro- the mothers pouch (Peters 1997; Chevalier et al. 2009). The
sis in experimental models (Miyazaki et al. 1998). Also, other alternative is to study the effect of UUO in the neonate
analysis of tissue obtained from the ureteropelvic junction of mouse, rat, rabbit or pig. In mice and rats, only 10% of the
patients which have undergone pyeloplasty (i.e. surgical nephrogenesis is completed at birth, corresponding to the
reconstruction or revision of the renal pelvis to drain and midtrimester in the human foetus and continues 10 days
decompress the kidney) have shown that the defective uri- after birth followed by a period of renal maturation. The
nary tracts present pathological changes in both smooth advantage of rodent models is the potential use of knockout
muscle rearrangement and pyeloureteral innervation (Zhang or transgenic animals to study the role of a specific molecule
et al. 2000). An interesting hypothesis has recently been pro- in the pathophysiology of obstruction and the relatively easy
posed to explain the role of smooth muscle cells in kidney access to these animals to increase statistical power. In rab-
maturation during late human gestation. In utero, the head bits and pigs, as in mice and rats, nephrogenesis is incom-
of the embryo usually rests in the mothers pelvis (Lye et al. plete at birth and continues for 2 and 3 weeks after birth,
2010). In this position urine must work against gravity and respectively. The advantage in pigs is that the kidney anat-
when peristalsis fails, this will lead to functional obstruction omy is close to the human anatomy. As opposed to the uni-
of the maturing kidney. papillary structure of the rodent kidney, pigs have
Although the molecular mechanisms underlying this multipapillary kidneys and predominantly short-looped
smooth muscle cell maldevelopment are still largely nephrons similar to humans (Eskild-Jensen et al. 2007).
unknown this seems, to date, to be the most probable cause Although very useful, the remaining question of these post-
of UPJ obstruction (Mendelsohn 2004). As this review natal models is whether the neonatal kidney reacts differ-
focuses on the renal consequences of UPJ obstruction, we ently to the obstruction compared to the foetal kidney.
will not discuss the (genetic) details of failure of the normal Indeed, the demand on renal function is much higher in neo-
smooth muscle development in the ureter and in the pelvis. nates than in foetuses where placenta is partly involved in
For more information in this field readers should refer to foetal blood dialysis (Peters 1997).
other excellent reviews (Mendelsohn 2004; Lye et al. 2010). Another issue is the technique employed to perform the
obstruction. Basically, there are two major ways to study
the effect of obstruction in foetuses and neonates: complete
Animal models of UPJ obstruction
or partial obstruction of the ureter. Complete obstruction is
Different animal models of UPJ obstruction exist, either most often performed by a simple suture ligation of the ure-
spontaneous or specifically developed, that mimic human ter. This model mimics severe UPJ obstruction and evolves
UPJ obstruction, each with specific merits and drawbacks. rapidly towards hydronephrosis and loss of renal paren-
Specific rodent strains have been identified that present chyma (12 weeks after UUO) (Chevalier et al. 2009). But,
reproducible lesions of spontaneous congenital hydronephro- since in the clinical situation most of the UPJ cases present
sis (Peters 2001). Although the underlying causes responsible partial rather than complete obstruction, partial UUO mod-
for this spontaneous UPJ obstruction phenotype remain els have been developed. One technique consists in wrapping
poorly understood, these models are interesting in that they the ureter into the underlying psoas muscle which allows the
are naturally occurring and reflect the human pathology obstruction to evolve with the growing animal but leads to
2010 The Authors. Journal compilation 2010 Blackwell Publishing Ltd, International Journal of Experimental Pathology, 92, 168192
170 J. Klein et al.
variable results. Another method consists in placing a stain- the associated histopathological changes (Matsell & Tarantal
less steel wire of known diameter parallel to the ureter, fol- 2002). Alterations affect renal growth, nephron number,
lowed by ligature of both the ureter and the stainless steel glomerular and tubulointerstitial histology, as well as the
wire. Subsequent withdrawing of the wire results in a well contralateral (i.e. non-obstructed) kidney.
calibrated partial obstruction. Not only this technique is
more reproducible than the psoas muscle approach but also, Renal growth. Partial and complete UUO in newborn
by choosing the different diameters of the stainless steel rodents is characterized by an enlarged pelvic diameter and
wire, the severity of the obstruction can be controlled (Che- increased kidney volume (Shi et al. 2004; Thornhill et al.
valier et al. 2009). 2005; Topcu et al. 2007; Guerin et al. 2008). UUO severely
affects kidney growth, as shown by decreased renal mass,
In conclusion, a number of animal models have been used protein or DNA content and parenchymal atrophy (Cheva-
to understand the pathophysiology of UPJ obstruction. lier et al. 1996; Chung & Chevalier 1996; Wen et al. 2002;
Clearly none of the individual models is perfect, but combin- Shi et al. 2004; Thornhill et al. 2005; Topcu et al. 2007;
ing data obtained in the different species and by different Guerin et al. 2008). UUO also inhibits nephrogenesis
techniques will help to better characterize the mechanisms thereby reducing the number of functional nephrons (Joseph-
involved in this pathology. son 1983; Chevalier et al. 1999; Wen et al. 2002; Thornhill
et al. 2005; Burt et al. 2007). Many of these effects are also
observed in neonatal pig model (Eskild-Jensen et al. 2002).
Renal consequences of UPJ obstruction In addition, and in contrast to human, variable partial UUO
in the neonatal rat shows that these lesions increase with the
Histological alterations
severity of the UUO (Thornhill et al. 2005).
The spectrum of renal abnormalities varies greatly in UPJ
obstruction. In human renal biopsies, one observes all Glomerular changes. In the neonatal model, partial or com-
lesions found in renal disease including subtle changes such plete UUO results in a decrease in the number of glomeruli,
as modified proximal or tubular size, chronic tubulointersti- not only by halting nephrogenesis but also by destruction of
tial injury, glomerulosclerosis, fibrosis, aberration of neph- previously formed glomeruli via apoptosis (Cachat et al.
ron development and in severe cases (<1%) renal dysplasia 2003; Eskild-Jensen et al. 2007) or phenotypic transforma-
(Rosen et al. 2008). tion of glomerular cells into mesenchymal cells (Thornhill
Studies have attempted to link the histological state of et al. 2005; Chevalier 2008). Glomerular maturation, evalu-
renal biopsy to the function of the obstructed kidney. How- ated by the number of capillary loops and the phenotype of
ever, no clear correlation between differential renal function podocytes, is delayed (Chevalier et al. 1999a, 2000a; Wen
and the gross histological status of the kidney was observed et al. 2002; Cachat et al. 2003; Burt et al. 2007; Chen et al.
(Elder et al. 1995; Stock et al. 1995; Han et al. 1998; 2007) and vascular tuft area is reduced (Chevalier et al.
Zhang et al. 2000). The only observation that seems to hold 1999a; Burt et al. 2007). Complete UUO increases the num-
is that severe UPJ obstruction (differential function of ber of renin secreting cells (Norwood et al. 1994) and main-
<30%) is associated with a high degree of parenchymal tains foetal renin distribution along the afferent arteriole
damage (Zhang et al. 2000). Also renal histology in humans rather confining renin expression to the juxtaglomerular
was found not to be related to the duration of obstruction apparatus (el-Dahr et al. 1991; Chung & Chevalier 1996).
(Han et al. 1998). This absence of a clear correlation In oppossum pups and in foetal lambs, a similar UUO-
between renal function and gross renal histology might be induced decrease in glomerular number is observed (Liapis
the cause of the observed high variability in the outcome of et al. 2000; Mure et al. 2006a), associated to podocyte foot
UPJ obstruction and the persisting difficulties in the clinical processes fusion (Fenghua et al. 2009) and cystic-like
assessment of UPJ obstruction (Csaicsich et al. 2004). How- changes such as dilatation of Bowmans space and collapsed
ever, detailed analysis of kidney histology in UPJ obstruc- capillary loops (Liapis et al. 2000; Mure et al. 2006a; Feng-
tion showed that subtle histological changes might be hua et al. 2009).
associated to impaired function of the obstructed kidney
(Huang et al. 2006). It was observed that in biopsies with Tubulointerstitial injury. Tubular damage is an important
little tubulointerstitial changes, the sizes of both proximal characteristic of UPJ obstruction, which is observed follow-
and distal tubules were significantly larger in UPJ obstruc- ing obstruction in neonatal rodents, foetal sheep and opos-
tion patients with significant functional obstruction (Huang sum pups. They include tubular apoptosis (Chevalier et al.
et al. 2006). 1999a, 2000a; Liapis et al. 2000; Cachat et al. 2003; Thorn-
In contrast to these observations in humans, alterations of hill et al. 2005; Lange-Sperandio et al. 2006, 2007; Yoo
renal parenchyma have been intensively studied in animal et al. 2006a; Burt et al. 2007; Eskild-Jensen et al. 2007a),
models of UPJ obstruction (Figure 1). Although these lesions tubular dilatation (Steinhardt et al. 1995; Chevalier et al.
can differ depending on the species or the severity of the 1999a; Liapis et al. 2000, 2001; Cachat et al. 2003), tubular
pathology, a general observation is that the earlier obstruc- atrophy (Chevalier et al. 1999a, 2000a; Fern et al. 1999;
tion occurs during in utero nephrogenesis, the more severe Lange-Sperandio et al. 2002, 2006, 2007; Thornhill et al.
Histological lesions Functional modifications

Afferent arteriole Arterioles
Altered renin distribution Decreased RBF
Glomerulus Glomerulus
Decreased glomeruli number Decreased GFR
Delayed maturation Proteinuria
Decreased vascular tuft area
Dilatation of Bowmans space
Podocyte foot processes fusion
Tubule Tubule
Tubulo-glomerular disconnection Decreased Na+ reabsorption

Tubular necrosis Decreased solute-free water reabsorption
Tubular basement membrane thickening Decreased urine concentrating capacity
Tubular apoptosis Decreased acid excretion and bicarbonate
Tubular atrophy regeneration under acid challenge
Tubular dilatation
Interstitium
Inflammation
Fibrosis
Decreased peritubular capillary density
Figure 1 Histological lesions and functional modifications induced by obstruction.
2005), tubular basement membrane thickening (Cachat et al. 2008). Interestingly, while alterations are rapidly induced
2003) and necrosis (Cachat et al. 2003). Progressive apopto- following complete UUO in foetal sheep, inflammatory cells
sis necrosis of tubules may promote glomerulotubular dis- are not visible. However, a marked inflammatory infiltrate,
connection leading to non functional nephrons (Thornhill associated with increased fibrosis, is observed if foetal
et al. 2005). Interestingly, each tubular segment responds obstruction continues after the birth (Mure et al. 2006a).
differently to complete UUO: apoptosis and dilatation are Consequently, the inflammatory response has probably not a
most consistently observed in collecting ducts and distal decisive role in the occurrence of renal alterations during
tubules, the tubular segments adjacent to the obstructed pel- foetal life (Mure et al. 2006a) and UUO induced-inflamma-
vis, whereas basement membrane thickening and necrosis tion in newborn rodents may be influenced by the renal
predominate in the proximal tubule (Cachat et al. 2003). functional demand imposed by extrauterine life (Matsell &
However, no overall changes in either proximal- or distal- Tarantal 2002).
tubule length are found in the obstructed kidney of newborn
pigs, explained by a combination of a reduction in length in The contralateral kidney. In response to partial and com-
damaged tubules and increased length in compensating plete UUO, the non-obstructed contralateral kidney develops
nephrons (Eskild-Jensen et al. 2002, 2007a). Finally, effect compensating hypertrophy (Norwood et al. 1994; Chevalier
of UUO on tubular proliferation is not clear because both 1996; Chevalier et al. 1996, 1999a,b; Fern et al. 1999;
increase (Cachat et al. 2003; Thornhill et al. 2005) and Malik et al. 2001; Chung & Wen et al. 2002; Cachat et al.
decrease (Chevalier et al. 1999a, 2000a) in proliferation 2003; Shi et al. 2004b; Topcu et al. 2007), the adaptative
were observed in the obstructed kidney. growth-rate increasing with the severity and duration of
Partial and complete UUO also modify the peritubular obstruction (Yoo et al. 2006a). Neither the number of
space of the obstructed kidney. The main interstitial modifi- glomeruli (Chevalier et al. 1999a; Cachat et al. 2003;
cations are enhanced inflammation (Chevalier et al. 1996; Thornhill et al. 2005; Burt et al. 2007) nor their maturation
Lange-Sperandio et al. 2002, 2006, 2007; Burt et al. 2007; index are modified (Chevalier et al. 2000a; Cachat et al.
Chen et al. 2007; Guerin et al. 2008), tubulointerstitial 2003). However, the mean glomerular area is higher than in
fibrosis (Steinhardt et al. 1995; Chevalier et al. 1999a,b, the control kidney (Chevalier et al. 1999a; Yoo et al. 2006a)
2000a; Fern et al. 1999; Liapis et al. 2000, 2001; Lange- and renin expression is inhibited (Norwood et al. 1994;
Sperandio et al. 2002, 2006, 2007; Cachat et al. 2003; Kiley Chevalier et al. 1996) while the number and the localization
et al. 2005; Mure et al. 2006a; Chen et al. 2007; Eskild-Jen- of renin cells are normal (Norwood et al. 1994; Chevalier
sen et al. 2007b; Guerin et al. 2008) and decreased peritubu- et al. 1999a). No particular modification is described in
lar capillary density. The latter has been shown to be tubules excepted proliferation which is sometimes observed
particularly prominent in the medulla during complete UUO (Cachat et al. 2003) and the number of peritubular capillar-
(Burt et al. 2007). ies is not changed (Burt et al. 2007).
Tubular and interstitial changes are closely correlated.
The number of apoptotic tubular cells was found to parallel In conclusion, nearly all histological alterations found in
fibrosis (Cachat et al. 2003; Guerin et al. 2008) and macro- humans in response to UPJ obstruction are found in the pre-
phage infiltration (Lange-Sperandio et al. 2002; Guerin et al. natal and neonatal animal UUO models suggesting that the
172 J. Klein et al.
observations in animal models have fair chance to be valid the solute-free water reabsorption (TcH2O) is markedly
in human UPJ obstruction. decreased in the obstructed kidney from partially obstructed
rats, indicating that the ability of these kidneys to reabsorb
water in collecting ducts is reduced. TcH2O does not seem
Functional modifications
to increase in the contralateral kidney and finally, urine
It is well established that UPJ obstruction induces mild to osmolarity decreases, showing an impaired urinary concen-
severe impairment of kidney function, including glomerular trating capacity in UUO animals (Shi et al. 2004a,b; Topcu
filtration and tubular exchanges of water and solutes. Stud- et al. 2007). These effects can be explained by looking at
ies in humans are lacking but how these mechanisms are the UUO-induced changes in transporters expression and
modified has been extensively studied in animal models of activity. Neonatal complete or partial UUO induces a reduc-
obstruction (Figure 1). Changes in the obstructed kidney, in tion in expression and distribution of major sodium trans-
the contralateral kidney and in the whole animal are vari- porters and water channels including Na,K-ATPase, NHE1,
able, depending on species, the duration and the severity of NHE3 and aquaporins (AQP1, AQP2, AQP3, AQP7), asso-
obstruction, but also depend on the diet and the hydration ciated to a down-regulation of the vasopressin 2 receptor
status. (Table 1) (Silverstein et al. 2003a; Shi et al. 2004a; Manu-
cha et al. 2007; Topcu et al. 2007; Wang et al. 2009). This
Renal blood flow. Limited data are available on the decrease of transporters expression could be regulated by
response of renal blood flow (RBF) to foetal neonatal UUO. dynamin, a key component of the endocytic machinery
In the neonatal rat, 424 weeks of partial UUO induces a involved in internalization of several transporters, as it was
progressive reduction in RBF in the obstructed kidney (Shi found frequently stimulated in UUO (Table 1) (Silverstein
et al. 2004b; Topcu et al. 2007; Wen et al. 2009). In foetal et al. 2003a; Padovano et al. 2009; Moeller et al. 2010;
lamb, chronic complete UUO also decreases RBF, this effect Ramstrom et al. 2010). In parallel to the regulation of trans-
being less severe when UUO is partial (Nguyen & Kogan porter expression, it seems also that the activity of the trans-
1998; Mure et al. 2006b). This diminution in RBF leads porters can be modified. Indeed, the mechano-sensitive gap-
most probably to ischemia, thus contributing in part to the junction protein connexin 30 participates in ATP release into
observed lesions of renal tissue. the tubular fluid and this inhibits salt and water reabsorp-
tion by the transporters (Sipos et al. 2009). Interestingly,
Glomerular filtration. In general, neonatal UUO results in connexin 30 expression is increased in the obstructed kidney
decreased glomerular filtration rate (GFR) in the obstructed (Table 1) (Silverstein et al. 2003b). Altogether, these results
kidney as seen in rats (Josephson 1983; Shi et al. 2004a,b; provide the molecular mechanism for the observed modified
Thornhill et al. 2005; Topcu et al. 2007) and pigs (Eskild- urine osmolality in neonatal UUO animals.
Jensen et al. 2000, 2001). When partial UUO persists, the
fall in GFR becomes more pronounced in the rat (Shi et al. Uremia, hydromineral and acido-basic status. Plasma urea
2004a) whereas it is attenuated in the pig model (Eskild-Jen- levels are identical in neonatal UUO and control rats (Shi
sen et al. 2000, 2001). In the non-obstructed contralateral et al. 2004a), indicating that the UUO-induced filtration
kidney, GFR may either increase (Josephson 1983; Eskild- defect is either not severe enough to induce hyperuremia or
Jensen et al. 2001, 2007b) or remain unchanged (Shi et al. counterbalanced by a defect in urea reabsorption. Moreover,
2004a; Thornhill et al. 2005; Topcu et al. 2007) and the in spite of the reduced ability to concentrate urine, animals
compensatory response of contralateral kidney depends also with neonatal UUO have normal natremia and osmolality
on the duration of obstruction (Eskild-Jensen et al. 2001). In (Shi et al. 2004a,b; Topcu et al. 2007) and are probably also
parallel proteinuria develops in the obstructed kidney and not dehydrated because arterial blood pressure is either
contralateral kidney following partial or complete UUO, unchanged (el-Dahr et al. 1991; Fern et al. 1999; Eskild-
respectively (Thornhill et al. 2005). Finally, total GFR in Jensen et al. 2007a) or increased (Topcu et al. 2007), but
obstructed animals can reach (Eskild-Jensen et al. 2001; not decreased.
Wang et al. 2009) or not (Shi et al. 2004a; Topcu et al. Partial UUO induces a transient increase in the expression
2007) the same level as GFR in the sham operated animals. of transporters involved in the acid base balance such as
NHE3, NBC1, Pendrin and Na,K-ATPase after 7 weeks of
Tubular function. Modification of tubular function in obstruction, as a compensatory mechanism to maintain sys-
response to UUO in neonatal rats was extensively studied temic acid-base balance (Table 1) (Wang et al. 2009). How-
and showed profound effects of UUO on the tubular han- ever, at later stages, this compensatory mechanism is failing
dling of water and solutes. Partial UUO is clearly associated and the expression of the transporters is dramatically
with a defect in sodium reabsorption since the fractional decreased. Interestingly in these animals, the acidbase equi-
excretion of sodium is increased in the obstructed kidney. librium is not modified as no changes in blood pH, bicar-
As a result, and in the absence of a compensatory change in bonates and CO2 pressure were observed (Wang et al.
the non-obstructed kidney, animals display natriuria in spite 2009). The consequences of the transporter down-regulation
of a decrease in the filtered sodium load (Shi et al. 2004a,b; are observed only when animals are subjected to acid load-
Eskild-Jensen et al. 2007a; Topcu et al. 2007). In addition, ing. During acid challenge, UUO rats fail to regulate acid
Table 1 Literature data about tubular transport and glomerular function-related genes and proteins that have been altered during
obstructive nephropathy. We have reported here only molecules of which activity or expression has been significantly modified com-
pared to sham-animals (animal model) or control cells (in vitro)
Animal model In vitro
Gene Fluid
symbol Gene name PUUO CUUO Ref Stretch flow Ref.
AQP1 Aquaporin 1 Down (24w) Shi et al. (2004a)

AQP2 Aquaporin 2 Down (10w) Topcu et al. (2007)
AQP3 Aquaporin 3 Down (24w) Shi et al. (2004a)
AQP7 Aquaporin 7 Down (2w) Silverstein et al. (2003a)
ATP1a1 Na+ K+ ATPase Down (7w to Shi et al. (2004a),
24w) Topcu et al. (2007),
Wang et al. (2009)
Avpr2 Vasopressin V2 receptor Down (2w) Silverstein et al. (2003a)
Calb1 Calbindin D28 Down (2w) Silverstein et al. (2003a)
Dnm1 Dynamin Up (2w) Silverstein et al. (2003a)
Gjb6 Connexin 30 Up (2w) Silverstein et al. (2003b)
Itga3 Integrin, alpha 3 Down Dessapt et al. (2009)
Itgb1 Integrin, beta 1 Down Dessapt et al. (2009)
Nphs1 Nephrin; nephrosis 1 homolog Down Miceli et al. (2010)
Scnn1a ENaC; epithelial Na+ channel Up* Satlin et al. (2001)
Slc12a3 Thiazide-sensitive Down (2w) Silverstein et al. (2003a)
sodium-chloride cotransporter
Slc20a1 Sodium-dependent phosphate Down (2w) Silverstein et al. (2003a)
transporter 1
Slc21a4 OAT-K1; kidney-specific anion Down (2w) Silverstein et al. (2003a)
transporter
Slc26a4 Pendrin; sodium-independent Up (7w) Wang et al. (2009)
chloride iodide transporter
Slc4a4 NBC1; anion exchanger, Up (7w) Down (14w) Wang et al. (2009)
member 4
Slc4a7 NBCn1; sodium bicarbonate Down (14w) Wang et al. (2009)
cotransporter, member 7
Slc9a1 NHE1; sodium hydrogen Down (2w) Manucha et al. (2007)
exchanger, member 1
Slc9a3 NHE3; sodium hydrogen Up (7w) Down (2w) Silverstein et al. (2003a),
exchanger, member 3 Wang et al. (2009)
u: urine; t: tissue; p: plasma; w: weeks of obstruction; d: days of obstruction; PUUO: partial UUO; CUUO: complete UUO; *activity;
Ref.: references.
excretion and bicarbonate regeneration and develop meta- corrected UPJ obstruction leads to improved renal function
bolic acidosis whereas control rats maintain normal blood compared to preoperative function in patients followed just
pH (Wang et al. 2009). after puberty (Chertin et al. 2009). Unfortunately in this
Finally, it is interesting to point out that other proteins or study the control group without pyeloplasty is missing.
transporters involved in the hydromineral balance such as Moreover, since long-term studies in humans are not avail-
the sodium dependent phosphate transporter, the thiazide able, the consequence of UPJ on adult renal function is not
sensitive sodium chloride transporter, the kidney specific known.
anion transporter OAT-K1 and calbindin D28, implicated in Once again, the use of experimental animal models has
calcium transport regulation, are also down-regulated during shed light on the renal consequences of UUO after surgical
experimental neonatal UUO (Table 1) (Silverstein et al. release. Studies in neonatal rodents have shown that after
2003a). 5 days of complete UUO and although primary stimulus for
injury was removed, structural lesions persist 1 month after
release: (i) glomerular number was still low (Chevalier et al.
Renal recovery after UPJ obstruction release
1999a), indicating that the loss of nephrons is definitive;
Although it has been observed that even delayed pyeloplasty (ii) renin expression was not confined to the juxtaglomerular
leads to recovery of short term renal function (Chertin et al. apparatus thus conserving its immature expression pattern
2006), what is the consequence of the UPJ-induced renal (Chevalier et al. 1999a); (iii) tubular deterioration was
lesions later in life? One recent study reports that surgically attenuated, but not reversed, since tubular atrophy with
174 J. Klein et al.
significant apoptotic lesions was still observed (Chevalier

et al. 1999a,b); (iv) fibrotic lesions remained; and (v) cyto-
Hydrodynamic modifications as potentially
kine growth factor expression did not returned to basal lev-
primary inducer of lesions
els (Chevalier et al. 1999a,b). An exception is in neonatal As tubular cells are first in line during the early phases of
mice, where the process of glomerulotubular disconnection neonatal UUO, what are the different types of stress encoun-
is arrested by release of obstruction (Thornhill et al. 2007). tered by these cells? The literature points out to two poten-
While most of the initial UUO lesions did not disappear tial candidates that can be involved in the primary induction
1 month after release of the obstruction, glomerular function of the renal lesions: tubular ischemia resulting from renal
was strongly improved with a normalized GFR (Chevalier hypoperfusion and pressure-induced compression or stretch-
et al. 1999a). However, tubular function was still perturbed. ing of tubular cells. However, these hypotheses mainly origi-
Indeed, urine flow rate and sodium excretion were increased nate from knowledge obtained from the adult UUO model.
in the post-obstructed kidney with normal GFR, indicating In this section, we will discuss whether these hypotheses are
that reduced reabsorption of water and sodium persisted still valid in neonatal UUO and we propose a new candi-
(Chevalier et al. 1999a). This suggests that modified renal date-process involved in the early phases of UUO-induced
transporter expression is not corrected after the release. lesions.
Surprisingly, although glomerular function 1 month after
release was improved, this amelioration was only transient
Tubular ischemia induced by renal hypoperfusion
as both GFR and tubular reabsorption were profoundly
impaired in the postobstructed kidney 3 months or 1 year The first candidate, often proposed to be an early inducer of
after release (Chevalier et al. 2000b, 2002). The contralat- renal lesions following obstruction, is tubular ischemia. In
eral kidney maintained a stable GFR, but hypertrophy, adult animals, UUO induces a rapid increase in renal blood
glomerulosclerosis, tubular atrophy, inflammation and inter- flow (RBF) caused by local prostaglandin E2 NO genera-
stitial fibrosis were observed. In addition the contralateral tion, which decreases the resistance of afferent arterioles.
kidney produced proteinuric urine (Chevalier et al. 2000b). However, this increase is transient as only 2 h after UUO
Thus there was progressive loss of renal function due to glo- RBF declines due to activation of the reninangiotensin
merular and tubulointerstitial damage at the level of rem- system (RAS) and or vasoconstrictor thromboxane. This
nant nephrons (Chevalier et al. 2000b). Partial UUO led to decreased RBF is associated with a prompt reduction in
a less severe phenotype since 6 months after 1 week-partial medullar tissue oxygen tension (Wilson 1980; Nguyen &
UUO, neither GFR nor sodium and solute-free water reab- Kogan 1998; Le Normand et al. 2005; Quinlan et al. 2008;
sorption are decreased in the postobstructed kidney (Shi Jensen et al. 2009).
et al. 2004b). In contrast, UUO in the foetal lamb leads to a delayed
As seen above for the earlier the obstruction the worse (1 week after UUO) and less dramatic fall in RBF than in
the outcome, also the earlier the release the better the out- adult UUO (Nguyen & Kogan 1998). Thus ischemia and
come holds. Experiments where partial or complete UUO related insults like hypoxia, nutrient depletion and waste
were induced during nephrogenesis and released at different accumulation are indeed potentially involved in the patho-
time-points showed that early release of neonatal obstruc- physiology of both adult and foetal neonatal obstruction.
tion provided a better protection of renal structure and func- However, due to differences in timing, it seems less relevant
tion than late release (Chevalier et al. 1999b; Shi et al. to consider ischemia as a primary and early inducer of renal
2004b). Moreover, when renal outcome was analysed lesions in foetal than in adult UUO.
1 month after temporary complete UUO performed either
during nephrogenesis or during maturation in neonatal rats,
Tubular compression and stretch
it appears that maturing kidneys are more sensitive to
obstructive injury immediately following the completion of In adult animals, UUO induces profound and rapid elevation
nephrogenesis than during ongoing nephrogenesis (Chevalier of intrapelvic pressure during the first hours following UUO,
et al. 2002). which is immediately transmitted to renal tubules. Indeed,
Overall, in humans the follow-up on UPJ obstruction micropuncture experiments indicate that during the first 2 h
patients, either surgically corrected or spontaneously resolv- following complete UUO, hydrostatic pressure is increased
ing UPJ obstruction shows that renal function is unaffected in the proximal tubule (Gottschalk & Mylle 1956; Dal Can-
upto at least shortly after puberty in the majority of the UPJ ton et al. 1977). Elevated intra-tubular pressure may have
obstruction population. However the gross and fine renal two consequences on the tubular cell. Either the tubular cell
histology in the human UPJ obstruction kidney and animal is exposed to compression, due to increased transmural pres-
experiments suggest that renal lesions are present at the sure or renal tubule is subjected to pressure-induced defor-
moment of severe obstruction that potentially have impor- mation, leading to increased stretch of the cells (Quinlan
tant effects on adult renal function as it has been shown et al. 2008). This increased pressure is only transient.
in animals (Chevalier et al. 2000b). Whether these animal Indeed, the combination of pelvic dilatation, reduction of
data are also valid in human UPJ obstruction remains to be RBF, reduction of glomerular filtration and continuous urine
studied. drainage by lymphatic and venous circulation, allows pelvic
pressure to rapidly decline until it reaches baseline levels associated to the tubular dilatation can lead to UUO-induced
(Wilson 1980; Nguyen & Kogan 1998; Quinlan et al. modifications of urinary shear stress and that shear stress
2008). This is accompanied by normalisation of intra-tubu- may therefore participate to pathophysiology of obstructive
lar pressure (Gottschalk & Mylle 1956; Dal Canton et al. nephropathy.
1979; Wilson 1980). Thus, although transitory, it is often
considered that stretch and compression of the tubular cells In conclusion, hydrodynamic fluid changes can potentially
are primary inducer of UUO-induced tubular lesions in lead to processes including tubular compression, stretch and
adults. urinary shear stress that contribute to the early induction
Complete UUO in foetal lamb also induces elevated pres- and progression of obstructive nephropathy (Figure 2).
sure as measured in the ureteral segment above the ligature. These issues have been studied on appropriate in vitro mod-
Interestingly, this increased pressure is not transient like in els and will be discussed within the following section. In
adults, but persists even 10 days after obstruction (Nguyen & contrast, because ischaemia seems to be involved in the later
Kogan 1998). This suggests that compression of tubular cells phases of neonatal and foetal UUO, the in vitro effects of
and stretch may also be considered as good candidates for ischaemia on tubular cells will not be reported. For this the
primary inducers of UUO-induced lesions. Different tubular reader is referred to other manuscripts (Heyman et al. 2008;
segments potentially respond differently to these mechanical Tanaka & Nangaku 2010).
stimuli. The low compliance of the proximal tubule (Cortell
et al. 1973) and the lack of tubular proximal dilatation in the
newborn mouse after chronic complete UUO (Cachat et al.
Molecular mechanisms: lessons from human
2003) suggest that proximal cells are resistant to stretch. In
studies and experimental models
contrast, distal tubules and collecting ducts have shown to be The majority of the research efforts in human UPJ obstruc-
highly compliant (Cortell et al. 1973) and dilate without tion have focused on inflammatory and profibrotic responses
marked cellular proliferation after foetal neonatal UUO as these were clearly identified events in UPJ obstruction
(Liapis et al. 2000; Cachat et al. 2003) resulting potentially in (Elder et al. 1995; Zhang et al. 2000). Although data is
tubular stretching. Thus, increased transmural pressure and scarce, it is confirming the general pathological mechanisms
mechanical stretch may be considered as primary inducers of observed in renal pathology associated to renal fibrosis
lesions in foetal neonatal model of UUO for proximal and including inflammation, activation of the RAS, profibrotic
distal parts of the renal tubule, respectively. cytokine induction, modification of tubular enzyme activity
and extracellular matrix accumulation. This information has
been largely complemented and confirmed by data obtained
Modification of urinary shear stress
in a variety of animal models of obstruction. Moreover, the
As discussed above, modifications of intra-tubular hydrody- effects of intra-tubular hydrodynamic forces modifications
namic forces induce compression and stretch of epithelial have been studied in vitro. Some limits of these experiments
cells. However, it has been recently suggested that another exist. Indeed, pressure studies are limited and the effect of
candidate can lead to renal lesion following urinary flow stretch has mainly been investigated on podocytes and proxi-
modifications (Essig et al. 2001; Rohatgi & Flores 2010). mal tubular cells with only a few studies describing the
Indeed, renal tubules are continually subjected to fluid shear effects of stretch on distal tubule cells. Moreover, in all these
stress corresponding to the frictional forces exerted by flow- studies, cells are not derived from foetal neonatal animals.
ing urine on the tubular wall. The intensity of shear stress However, these in vitro experiments can give some clues to
depends on fluid viscosity, fluid flow rate (i.e. glomerular fil- understand the molecular mechanisms involved in the
tration rate) and tubular diameter (i.e. level of tubular dila- progression of obstructive nephropathy.
tation).
Little is known about early changes of GFR during foetal
Inflammation
and neonatal obstruction. Indeed, although it is known that
neonatal or foetal chronic UUO induces GFR fall (Josephson Chronic neonatal obstructive nephropathy is associated
1983; Eskild-Jensen et al. 2000, 2001; Shi et al. 2004a,b; with massive interstitial macrophage infiltration. The
Thornhill et al. 2005; Topcu et al. 2007), variations of GFR recruitment of inflammatory cells is mediated in part by
during the first phases of the pathology were not studied. increased secretion of chemokines by stressed tubular cells.
However in adults, GFR is shortly maintained in the first The chemokine CCL2 (MCP-1) is a powerful chemotactic
hours of obstruction, most probably since the increase in agent and is involved in monocyte activation (Leonard &
intra-tubular pressure is compensated by increased RBF and Yoshimura 1990). Patients with UPJ obstruction had four-
glomerular capillary pressure (Dal Canton et al. 1977). fold higher CCL2 concentrations in their urine than healthy
Then, a marked decrease of GFR occurs, due to reduction of controls. This was correlated with a significant increase in
both glomerular capillary pressure and RBF induced by MCP-1 expression on renal biopsies as shown by in situ
vasoconstriction of afferent arterioles (Gottschalk & Mylle hybridization (Table 2) (Grandaliano et al. 2000). Four
1956; Dal Canton et al. 1979). Altogether these results sug- months after pyeloplasty, urinary MCP-1 concentrations
gest that the potential reduction of GFR, as seen in adults, decreased close to levels of control individuals. In experi-
176 J. Klein et al.
Normal kidney
Shear
GFR Pressure
stress
UUO
Elevated tubular pressure
Obstructed kidney
Decreased GFR
Decreased shear stress
Attenuated hyperpressure
Dilatation
Tubular stretch
Decreased shear stress
Normalized pressure
Figure 2 Renal tubular exposure to hydrodynamic modifications following obstruction. Following intra-pelvic urine accumulation,
UUO induces rapid elevation of hydrostatic pressure into the renal tubular lumina, leading to stretch and compression of the tubular
cells and thus to tubular dilatation. As GFR declines and tubular dilatation increases, hyperpressure progressively returns to basal lev-
els. However in the mean time, fluid shear stress, which depends on both GFR and tubular diameter, is strongly reduced. Thus modi-
fications of renal hydrodynamics can induce mechanical stimuli such as pressure, shear stress and stretch. These three factors are
potential insults for tubular cells and can be involved in the primary induction of the UUO-induced renal lesions.
mental models, complete neonatal obstruction also induced able on adhesion molecules during UPJ in children.
up-regulation of CCL2 together with other chemokines Finally, obstruction is also characterized by induced
including CCL3 (MIP-1a), CCL4 (MIP-1b) and CCL5 expression of transcription factors known to be involved in
(RANTES) (Table 2) (Silverstein et al. 2003a; Lange-Sper- inflammation, such as interferon regulatory factor-1 (IRF-1)
andio et al. 2007). Macrophage infiltration is also induced and nuclear factor-jB (NF-jB) (Table 2) (Silverstein et al.
by up-regulation of adhesion molecules on endothelial and 2003a; Topcu et al. 2007) and of members of the pro-
inflammatory cells. It has been shown that neonatal UUO inflammatory tumour necrosis factor superfamily. In chil-
in mice induced renal expression of intercellular adhesion dren, expression of the cytokine tumour necrosis factor-a
molecule-1 (ICAM-1), receptor for advanced glycation (TNFa) is increased in urine during UPJ obstruction
end-products (RAGE) and junction adhesion molecule-C (Valles et al. 2003) whereas in neonatal rats, mRNA
(JAM-C) adhesion molecules (Table 2) (Lange-Sperandio expression of Fas and Fas ligand is induced in the
et al. 2006). Moreover, Mac-1 (aMb2, CD11b CD18) b2 obstructed kidney compared to the sham (Silverstein et al.
integrin knockout, LFA-1 (aLb2, CD11a CD18) b2 integrin 2003a) (Table 2).
knockout, L-selectin knockout or L-, P-, and E-selectin Effects of mechanical stretch on inflammatory mediators
triple knockout mice are protected from inflammation have been studied in vitro, mainly in pulmonary epithelial
induced by neonatal UUO (Table 2) (Lange-Sperandio cells but not in tubular epithelial cells. Nevertheless, the fact
et al. 2002, 2006). To our knowledge, no data are avail- that stretch modifies adhesion molecules expression, such as
Table 2 Literature data about inflammation-related genes and proteins that have been altered during obstructive nephropathy. We
have reported here only molecules of which expression has been significantly modified compared to healthy control (human), sham-
animals (animal model) or control cells (in vitro)

Gene
symbol Gene name Human Ref. PUUO CUUO Ref. Stretch Ref.
Ager RAGE; receptor for Up (1d) Lange-Sperandio

advanced glycosylation et al. (2006)
end products
Ccl2 Chemokine (C-C motif) Up (u, t) Grandaliano Up (2w) Silverstein
ligand 2; MCP-1 et al. (2000) et al. (2003a)
Ccl3 Chemokine (C-C motif) Up (5d) Lange-Sperandio
ligand 3; MIP-1a et al. (2007)
ligand 4; MIP-1b et al. (2007)
ligand 5; RANTES et al. (2007)
Cd14 Monocyte differentiation Up (2w) Silverstein
antigen CD14 et al. (2003a)
Fas TNF receptor Up (2w) Silverstein
superfamily, member 6 et al. (2003a)
Faslg Fas ligand Up (2w) Silverstein
et al. (2003a)
Icam1 Intercellular adhesion Up (5d) Lange-Sperandio Up Hu et al. (2008)
molecule 1 et al. (2006)
IL8 Interleukin 8; CXCL8 Up Vlahakis et al. (1999),
Yamamoto et al. (2001),
Oudin and Pugin (2002)
Irf1 Interferon regulatory Up (2w) Silverstein
factor 1 et al. (2003a)
Jam3 JAM-C; junction Up (5d, 2w) Lange-Sperandio
adhesion molecule 3 et al. (2006)
Nfkb1 NF-jB Up (10w) Topcu et al. (2007)
Tnf Tumor necrosis Up (u) Valles Up Dixon et al. (2008)
factor; TNF-a et al. (2003)
u: urine; t: tissue; p: plasma; w: weeks of obstruction; d: days of obstruction; PUUO: partial UUO; CUUO: complete UUO; Ref.: references.
ICAM-1 (Hu et al. 2008) and cytokine production, such as as epithelial to mesenchymal transition (EMT). During
TNFa (Dixon et al. 2008) and interleukin-8 (Vlahakis et al. EMT, tubular epithelial cells loose progressively their epithe-
1999; Yamamoto et al. 2001; Oudin & Pugin 2002) lial phenotype, detach from the surrounding cells, digest the
(Table 2) in other epithelial cell types suggests that it may basal membrane and migrate into the interstitium where
also trigger inflammatory signalling in renal tubules and thus they acquire mesenchymal properties (Liu 2010). Well-
participate to progression of obstructive nephropathy. described in vitro, the existence of EMT in vivo and its real
participation to the fibrotic process is still under debate.
However, some characteristic features of EMT have been
Fibrosis
found during experimental UUO (Table 3): increased expres-
In almost all form of renal diseases, chronic inflammation is sion of essential signalling proteins such as Snail1, Snail2 -
associated with the development of tubulointerstitial lesions Slug and beta-catenin (Lange-Sperandio et al. 2007);
of fibrosis. Fibrosis is defined by increased extracellular decreased expression of E-Cadherin, an epithelial protein
matrix (ECM) accumulation, due to both enhanced synthe- involved in cell-cell adhesion (Lange-Sperandio et al. 2007);
sis and decreased degradation of matrix proteins such as col- increased expression of MMP2 (matrix metalloprotease 2)
lagens and fibronectin. Myofibroblasts are the major and MMP9 (matrix metalloprotease 9), two enzymes
extracellular matrix (ECM) producing cells. They play an involved in the degradation of the tubular basal membrane
important role in the fibrotic process and their renal accu- (Mure et al. 2006a); and increased expression of mesen-
mulation in UPJ obstruction was evidenced by increased chymal markers such as desmin, calponin, vimentin and
interstitial a-smooth muscle actin and vimentin staining a-smooth muscle actin (Silverstein et al. 2003a; Lange-
(Murer et al. 2006). In the kidney, myofibroblasts are sup- Sperandio et al. 2007). Some markers have also been
posed classically to arise from the proliferation and activa- observed in renal tubular cells submitted to mechanical
tion of resident fibroblasts, but also from a process known stretch (Sato et al. 2003).
178
Table 3 Literature data about fibrosis-related genes and proteins that have been altered during obstructive nephropathy. We have reported here only molecules of which
expression has been significantly modified compared to healthy control (human), sham-animals (animal model) or control cells (in vitro)

Gene
J. Klein et al.
symbol Gene name Human Ref. CUUO Ref. Stretch Shear stress Ref.
Acta2 a-SMA; actin, alpha, vascular Up (t) Murer et al. (2006) Up (5d) Lange-Sperandio et al. (2007)
smooth muscle
Cdh1 Cadherin 1; E-cadherin Down (5d) Lange-Sperandio et al. (2007)
Cnn1 Calponin 1 Up (2w) Silverstein et al. (2003a)
Col5a2 Collagen, type V, alpha 2 (fragments) Up (u) Decramer et al. (2006)
Col9a3 Collagen, type IX, alpha 3 (fragments) Up (u) Decramer et al. (2006)
Ctnnb1 b-Catenin; catenin (cadherin Up (5d) Lange-Sperandio et al. (2007)
associated protein), beta 1
Dcn Decorin Up (2w) Silverstein et al. (2003a)
Des Desmin Up (2w) Silverstein et al. (2003a)
Egr1 Early growth response 1; Krox24 Up (2w) Silverstein et al. (2003a)
Mmp1 Matrix metalloproteinase 1 Up (6w) Mure et al. (2006a)
Mmp2 Matrix metallopeptidase 2 Up (6w) Mure et al. (2006a)
Mmp9 Matrix metallopeptidase 9 Up (6w) Mure et al. (2006a)
Pdgfa PDGF-A Up (10d, 20d) Liapis et al. (2000)
Plat tPA; plasminogen activator, tissue Up Essig et al. (2001)
Plau uPA; plasminogen activator, urokinase Up Essig et al. (2001)
Snai1 Snail1; snail homolog 1(Drosophila) Up (5d) Lange-Sperandio et al. (2007)
Snai2 Snail2; Slug; snail Homolog 2 Up (5d) Lange-Sperandio et al. (2007)
(Drosophila)
Tgfb1 TGFb; transforming Up (u, t) Furness et al. (1999), Up (5d to 4w) Chung and Chevalier (1996), Up Miyajima et al. (2000a,b),
growth factor, beta 1 El-Sherbiny et al. (2002), Yang et al. (2001), Dessapt et al. (2009)
Murer et al. (2006), Silverstein et al. (2003a),
Yang et al. (2006), Lange-Sperandio et al. (2007)
Taha et al. (2007a)
Tgfbr1 TGFbRI; transforming Up (10d) Yang et al. (2001) Up Miyajima et al. (2000a,b),
growth factor, beta receptor I Durvasula et al. (2004),
Dessapt et al. (2009),
Tgfbr2 TGFbRII; transforming Up (10d) Yang et al. (2001) Up Miyajima et al. (2000a,b),
growth factor, beta receptor II Durvasula et al. (2004),
Dessapt et al. (2009)
Timp1 Tissue inhibitor of metallopeptidase 1 Up (6w) Mure et al. (2006a)
Timp2 Tissue inhibitor of metalloproteinase 2 Up (6w) Mure et al. (2006a)
Vim Vimentin Up (t) Murer et al. (2006) Up (5d) Lange-Sperandio et al. (2007)
u: urine; t: tissue; p: plasma; w: weeks of obstruction; d: days of obstruction; CUUO: complete UUO; Ref.: references.
Renal collagen accumulation, as a consequence of myofi- stretch stimulates TGFb signalling with increased TGFb and
broblast appearance, has been frequently observed during TGFb receptors expression and TGFb secretion (Table 3)
human UPJ obstruction, but only using classical histology (Miyajima et al. 2000a,b; Durvasula et al. 2004; Dessapt
(H&E and Masson-trichrome) therefore lacking the identifi- et al. 2009). Moreover in non-renal cells, decorin mRNA
cation of the specific ECM components (Elder et al. 1995; expression is modified by mechanical stretch suggesting
Zhang et al. 2000). We have observed using urinary prote- that it may also be the case in renal tubular cells (Table 3)
ome analysis increased secretion of collagen Va and IXa3 (Ludwig et al. 2004; Ozaki et al. 2005). Altogether, these
fragments (Decramer et al. 2006) in UPJ obstruction patients data suggest that TGFb is a major mediator of renal injury
but the origin, renal or urinary tract, of these fragments is (i.e. fibrosis) during UUO.
currently unknown. Collagen accumulation is also described
during experimental UUO (Chevalier et al. 2009) and exper-
Nitric oxide and oxidative stress
iments of UUO in the foetal lamb have shown increased
expression of tissue inhibitors of metalloproteases (TIMP-1 Nitric oxide produced by the various forms of nitric oxide
and TIMP-2) (Table 3), which inhibit ECM degradation (NO) synthase (NOS) has been shown to be involved in the
(Mure et al. 2006a). Interestingly, exposing cultured proxi- evolution of experimental obstructive nephropathy.
mal cells to shear stress modifies both expression and activ- Increased NOS activity was also observed in humans with
ity of tPA (tissue type-plasminogen activator) and uPA UPJ obstruction originating from both endothelial NOS
(urokinase), two proteases strongly involved in ECM remod- (eNOS) and inducible NOS (iNOS) (Table 4) (Miyajima
elling suggesting that modification of shear stress during et al. 2000b; Valles et al. 2003, 2007). NOS activity is
obstruction could be involved in the development of fibrosis involved in a number of important processes in the kidney
(Table 3) (Essig et al. 2001). including glomerular haemodynamics and sodium and water
Renal fibrosis is regulated by different cytokines and excretion (Kone & Baylis 1997) that are strongly modified
growth factor. Among them, transforming growth factor in the different phases of UPJ obstruction (see above). Modi-
beta (TGFb) is the most potent pro-fibrogenic cytokine fication of NOS activity has also been studied during experi-
involved in renal diseases and is clearly associated to human mental UUO in neonates (Table 4). Very interestingly, NO
and experimental obstruction. A number of studies showed expression differs depending on the severity (i.e. complete
that urinary TGFb levels are increased in human UPJ vs. partial) and on the duration of the obstruction. For
obstruction (Table 3) (Furness et al. 1999; El-Sherbiny et al. example, increased renal NO was associated with iNOS up-
2002; Taha et al. 2007a). In addition, urinary TGFb concen- regulation 1 week after complete UUO in the neonatal rat
trations from UPJ obstruction patients were 24-fold higher (Manucha & Valles 2008), whereas both the NO level and
in the pelvis than in the bladder (Furness et al. 1999; eNOS and iNOS expression were reduced at a later stage
El-Sherbiny et al. 2002), suggesting that the urinary TGFb (2 weeks) (Silverstein et al. 2003a; Manucha & Valles
found in the bladder is mainly coming from the obstructed 2008). Decreased NO levels were associated with decreased
kidney. This is further corroborated in renal biopsy studies anti-apoptotic Bcl2 expression and increased pro-apoptotic
where increased TGFb expression was observed in UPJ caspase 3 activity leading to the conclusion that NO is pro-
obstruction (Murer et al. 2006; Yang et al. 2006). A decline tective during complete neonatal UUO. In mice, while the
of TGFb urinary levels is detected after surgery, but the fact protective and anti-apoptotic role of iNOS activity has been
that TGFb urinary levels decrease more slowly that urinary also demonstrated during complete obstruction (Yoo et al.
MCP-1 concentrations (Taha et al. 2007b) suggests that the 2010), it has been shown that NO has opposite effects dur-
inflammatory response resolves more rapidly than the fibro- ing partial obstruction and seems to aggravate renal mor-
tic response. In experimental UUO, both TGFb and TGFb phological alterations. After 1 week, partially obstructed
receptors (TGFbRI and TGFbRII, Table 3) are up-regulated iNOS knockout mice showed reduced renal pelvic dilatation
in the obstructed kidney compared to sham (Chung & Che- and preserved renal papilla compared to wild-type mice
valier 1996; Yang et al. 2001; Silverstein et al. 2003a; although they displayed similar tubular apoptosis (Yoo et al.
Lange-Sperandio et al. 2007). Decorin is an endogenous 2010). This discrepancy between complete or partial
inhibitor of TGFb expression and activity (Mogyorosi & obstruction could be explained by the differential action of
Ziyadeh 1999; Wu et al. 2007). It is assumed that increased iNOS and NO on renal parenchyma (anti-apoptotic) and on
expression of decorin associated with increased TGFb the ureteropelvic junction (inhibition of smooth muscle con-
expression may provide a regulatory mechanism to limit the traction). While inhibition on ureteral contractile activity in
TGFb induced injury (Diamond et al. 1997; Mogyorosi & complete UUO is without effect on urine retention, it can
Ziyadeh 1999). Very interestingly, it has been shown that modify the response to partial UUO. This is exemplified by
during complete UUO in neonatal rats, the up-regulation the fact that, in partial neonatal obstruction, iNOS knockout
of TGFb mRNA parallels decorin expression (Table 3) mice showed less hydronephrosis compared to wild-type
(Silverstein et al. 2003a) and even after release of UUO, as mice because pelvic urine drainage is increased (Yoo et al.
in humans, overexpression of TGFb-1 persists (Chevalier 2010).
et al. 1999a). In vitro experiments on podocytes or proximal In vitro experiments indicate that renal NO pathway is
cells indicate that under certain conditions, mechanical controlled by mechanical forces. Indeed, increased luminal
180 J. Klein et al.
flow stimulates NO release and induces eNOS activation

Table 4 Literature data about NO and oxidative stress-related genes and proteins that have been altered during obstructive nephropathy. We have reported here only mole-
Miyajima et al. (2000a),
Broadbelt et al. (2007)

Hegarty et al. (2002),
and translocation to apical membrane in the rat microper-
Ricardo et al. (1997)

fused ascending limb (Ortiz et al. 2004). However, in order
to determinate if this effect is caused by stretch, transmural
cules of which activity or expression has been significantly modified compared to healthy control (human), sham-animals (animal model) or control cells (in vitro).
pressure or shear stress modifications, experiments have been

carried out studying individual change of each parameter.
First, in vitro application of elevated hydrostatic pressure
Ref.
(Broadbelt et al. 2007) or stretch (Miyajima et al. 2000b;

Hegarty et al. 2002) to proximal cells increases iNOS
expression and NO production (Table 4). Interestingly, the
Pressure
effect of stretch seems to be species-dependent as the NO

Up*
increase is induced in rat but not in human cells (Miyajima

et al. 2000b; Hegarty et al. 2002). Moreover, NO donors
attenuate both stretch-induced apoptosis and proliferation
Shear stress
inhibition whereas NO inhibitors amplify them. These

in vitro results confirm that NO exerts a protective effect for
the severely obstructed stretched kidney (Miyajima et al.
u: urine; t: tissue; p: plasma; w: weeks of obstruction; d: days of obstruction; CUUO: complete UUO; *activity; Ref.: references. 2001; Hegarty et al. 2002). Second, increased shear stress
has been shown to increase NO production in medullary
Up* =*
Stretch
In vitro
collecting duct cells (Cai et al. 2000). This latter result is

Down
more difficult to directly transpose to the in vivo UUO situa-

tion where the shear stress is not increased but decreased
due to GFR decline and tubular dilatation (see above). How-
Valles (2008)
et al. (2003a)
ever it suggests that tubular NO production could be also

Valles (2008)
Valles (2008)
Manucha and
Manucha and
Manucha and
sensitive to urinary shear stress variations.

Silverstein
Another consequence of chronic UUO in newborns is the

increase of oxidative stress. In vitro, cellular stretch
Ref.
increases superoxide production and down-regulates catalase

mRNA levels (Table 4) (Ricardo et al. 1997; Garvin &
Animal model
Hong 2008). In vivo, 2 weeks of complete UUO in neonatal

Down* (2w)
Down (2w)
Down* (5d)
Down (2w)
Up* (2w)
rats induced NADPH oxidase activity and decreased super-

CUUO
Up (5d)
oxide dismutase activity (Table 4) (Manucha & Valles

2008). The role of NADPH oxidase-mediated ROS genera-
tion has been extensively studied in vivo and in vitro. Stud-
ies have shown that it can promote apoptosis or
et al. (2003),
et al. (2003)
et al. (2007)
proliferation of renal cells, such as mesangial cells, podo-

cytes and tubular cells (Jiang 2009). Moreover, NADPH
oxidase mediates proximal tubular cell death induced by
Valles
Valles
Valles
angiotensin II (Ang II) (Jiang 2009). Consistently with these

Ref.
results up-regulation of NADPH oxidase activity paralleled

the increase of apoptosis during experimental UUO support-
Human
Up* (t)
Up* (t)
ing the deleterious role of oxidative stress during neonatal

obstructive nephropathy (Manucha & Valles 2008).
Apoptosis and proliferation

synthase 2, inducible
synthase, inducible
eNOS; nitric oxide
iNOS; nitric oxide
During obstruction, tubular stretch, inflammation and oxida-

SOD; superoxide
NADPH oxidase
tive stress induce a severe apoptotic response of both tubular

Gene name
dismutase
and interstitial cells. Indeed urinary tubular enzymes poten-

Catalase
tially released by those cells including N-acetyl-b-d-glucosa-

minidase (Carr et al. 1994), alkaline phosphatase and
c-glutamyl transferase (Shokeir & Taha 2009) have been
found increased in human UPJ obstruction (Table 5). The
Gene symbol
role of other intracellular mediators of apoptosis or cell sur-

vival in obstruction has been investigated in animal models.
Nox1
Nos2
Nos3
In rats, mice and opossums complete and partial UUO stim-

Sod1
Cat
ulated expression and activity of pro-apoptotic molecules
Table 5 Literature data about apoptosis and proliferation-related genes and proteins that have been altered during obstructive nephropathy. We have reported here only mole-
cules of which activity or expression has been significantly modified compared to healthy control (human), sham-animals (animal model) or control cells (in vitro)
Gene symbol Gene name Human Ref. PUUO CUUO Ref. Stretch Ref.
Alpl Alkaline phosphatase Up* (u) Shokeir and

Taha (2009)
Anxa5 Annexin V Up Dessapt et al. (2009)
Bad BCL2-associated agonist of Up* (7d) Kiley et al. (2003) Up* Kiley et al. (2003)
cell death
Bcl2 B-cell CLL lymphoma 2 Down (2w) Steinhardt et al. (1995),
Manucha et al. (2007),
Manucha and Valles (2008),
Casp3 Caspase 3 Up (2w, 4w) Up* (2w, 4w) Manucha et al. (2007), Up* Dessapt et al. (2009)
Guerin et al. (2008),
Manucha and Valles (2008)
Clu Clusterin Up (2w) Chevalier et al. (1996),
Silverstein et al. (2003a)
Cycs Cytochrome C Up Kiley et al. (2003)
Dcn Decorin Up (2w) Silverstein et al. (2003a)
Fas TNF receptor superfamily, Up (2w) Silverstein et al. (2003a)
member 6
Faslg Fas ligand Up (2w) Silverstein et al. (2003a)
Ggt1 g-Glutamyl transferase Up* (u) Shokeir and Taha
(2009)
Hexa Hexb N-acetyl-b-D-glucosaminidase; Up* (u) Carr et al. (1994),
Hexoaminidase Shokeir and Taha
(2009)
Hspa4 HSP70; heat shock protein 4 Up (5d, 2w) Manucha and Valles (2008)
Hspb1 HSP27; heat shock protein 1 Up (2w) Silverstein et al. (2003a)
JunD jun D proto-oncogene Up (2w) Silverstein et al. (2003a)
Nfkb1 NF-jB Up (10w) Topcu et al. (2007)
Slc9a1 NHE1; Sodium hydrogen Down (2w) Manucha et al. (2007)
exchanger, member 1
Sparc Secreted protein, acidic, Up Durvasula and
cysteine-rich (osteonectin) Shankland (2005)
Tp53 p53; tumor protein p53 Up (2w) Silverstein et al. (2003a)
u: urine; t: tissue; p: plasma; w: weeks of obstruction; d: days of obstruction; PUUO: partial UUO; CUUO: complete UUO; *: activity; Ref.: references.
Congenital UPJ obstruction
181
182 J. Klein et al.
such as Bad, Caspase 3, Fas, Fas ligand and p53, together et al. 2003, 2005; Durvasula et al. 2004; Dessapt et al.
with down-regulation of anti-apoptotic Bcl2 and heat shock 2009). This effect is associated with elevated markers of
protein 70 (HSP70) (Table 5) (Steinhardt et al. 1995; Kiley early apoptosis such as dephosphorylated BAD, released
et al. 2003; Silverstein et al. 2003a; Manucha et al. 2007; mitochondrial cytochrome C, caspase-3 activity and annexin
Guerin et al. 2008; Manucha & Valles 2008). Ceramide, V (Table 5) (Kiley et al. 2003; Dessapt et al. 2009). In addi-
an endogenous lipid also considered as an intracellular medi- tion, the sodium proton exchanger NHE is also sensitive to
ator of cell death (Saba et al. 1996) was induced during neo- mechanical stress, as described in cardiomyocytes but not
natal UUO and paralleled apoptosis (Malik et al. 2001). yet in renal cells (Yamazaki et al. 1998). Underlying mecha-
Moreover, clusterin, which is a small heat shock protein-like nisms seem to be dependent on the cell type since stretch-
involved in pro-apoptotic mechanisms induced by oxidative induced apoptosis is mediated by TGFb in rat proximal cells
stress (Chevalier et al. 1996, 1999a; Silverstein et al. 2003a; (Miyajima et al. 2000a) whereas it is driven by type 1 angio-
Trougakos & Gonos 2006), is induced during experimental tensin II receptor in mouse podocytes (Durvasula et al.
UUO (Table 5). Interestingly, clusterin over-expression per- 2004). In addition stretch dependent apoptosis is greater in
sists even after the release of obstruction (Chevalier et al. the collecting duct than in proximal tubules (Cachat et al.
1999a). Some other molecules that are modified during 2003). This result can explain why in neonatal experimental
UUO have been described to be involved in the regulation of UUO, apoptosis is more severe in collecting ducts than in
apoptosis (Table 5): in addition to its inhibitory effect on proximal tubules (Cachat et al. 2003). Stretch not only pro-
TGFb activity, decorin has been found to induce apoptosis motes apoptosis, it also decreases proliferation as demon-
on mesangial cells in vitro (Wu et al. 2008); heat shock pro- strated in cultured mouse podocytes and HK-2 or MDCK
tein 27 (HSP27) is a crucial chaperone protein activated in cells (Hegarty et al. 2002, 2003; Petermann et al. 2002,
response of renal epithelial cellular stress to limit apoptosis 2005). In mice, this anti-proliferative effect is mediated
(de Graauw et al. 2005); JunD, one of the components of through the reduction of cyclins levels and their partner
the AP-1 transcription factor complex has been shown to CDKs associated to increment in CDK-inhibitors expression
promote cell survival in epithelial renal cells in vitro (Silver- (Petermann et al. 2002). It is also associated to increased
stein et al. 2003a; Lu et al. 2009); the sodium proton SPARC (secreted protein acidic and rich in cystein) levels
exchanger-1 (NHE1) is involved in renal sodium transport (Table 5), a protein which in vivo diminishes proliferative
but is also a caspase substrate and its proteolytic cleavage capacity of various tissues via inhibition of mitogenic
promotes progression towards apoptosis (Manucha et al. growth factors (Durvasula & Shankland 2005).
2007; Schelling & Abu Jawdeh 2008).
The apoptotic response to mechanical stretch has been
The reninangiotensin system and associated partners
extensively studied in vitro. Stretch increases apoptosis or
susceptibility to apoptosis in murine, human and canine epi- Activation of the renin-angiotensin system (RAS) has been
thelial renal cells (Miyajima et al. 2000a, 2001; Nguyen observed in many renal diseases. Also UPJ obstruction does
et al. 2000; Hegarty et al. 2002; Cachat et al. 2003; Kiley not escape this fate. In mice and rats, renal expression of
Table 6 Literature data about reninangiotensin system (and associated)-related genes and proteins that have been altered during
obstructive nephropathy. We have reported here only molecules of which activity or expression has been significantly modified com-
pared to healthy control (human), sham-animals (animal model) or control cells (in vitro)

Gene
symbol Gene name Human Ref. CUUO Ref. Stretch Ref.
Agtr1 Angiotensin II = (t) Murer et al. (2006), Down (1d) Yoo et al. (1997) Up Durvasula et al. (2004)
receptor, type 1 Valles et al. (2007) Up (4w) Kolb et al. (2004)
Agtr2 Angiotensin II = (t) Murer et al. (2006), Down Yoo et al. (1997) = Durvasula et al. (2004)
receptor, type 2 Valles et al. (2007) (1d; 4w)
Bdkrb2 Bradykinin receptor B2 Up (4w) Chen et al. (2007)
Gja4 Connexin 37 Up (2w) Silverstein et al. (2003b)
Gja5 Connexin 40 Up (2w) Silverstein et al. (2003b)
Pcsk1n proSAAS; Down (u) Decramer
proprotein et al. (2006)
convertase 1 inhibitor
Ren Renin Up* (p) Bajpai Up el-Dahr et al. (1991), Up Ricardo et al. (2000)
et al. (2007) (2w, 4w) Chevalier et al. (1996),
Chung and Chevalier (1996),
Yoo et al. (1997),
Silverstein et al. (2003a)
u: urine; t: tissue; p: plasma; w: weeks of obstruction; d: days of obstruction; CUUO: complete UUO; *activity; Ref.: references.
renin is up-regulated in neonatal models of complete UUO induced cellular effects including apoptosis, down-regulation
compared to the sham operated kidney (Table 6) (el-Dahr of nephrin (see below tubular transport and glomerular
et al. 1991; Chevalier et al. 1996; Chung & Chevalier 1996; function) or stimulation of osteopontin expression (see
Yoo et al. 1997; Silverstein et al. 2003a) and this is corre- below other cytokines and growth factors) are mediated by
lated with increased angiotensin II (AngII) content in the the AT1-R (Diamond et al. 1998; Ricardo et al. 2000;
obstructed kidney (Yoo et al. 1997). In children, plasma Durvasula et al. 2004; Miceli et al. 2010). Interestingly,
renin activity was observed to gradually increase with the Caveolin-1 is also a stretch sensitive protein, as demon-
time of UPJ obstruction and showed to precede parameters strated in non-renal murine cells, where translocation of
of actual renal injury including split renal function and glo- caveolin-1 from caveolar to non-caveolar sites within the
merular filtration rate. In addition plasma renin activity was plasma membrane or from the plasma membrane to cyto-
reduced postoperatively (Bajpai et al. 2007). We have plasm can be observed in response to stretch (Kawabe et al.
observed decreased urinary excretion of proprotein conver- 2004; Wang et al. 2010). As stretch, shear stress alters the
tase subtilisin kexin type 1 inhibitor (proSAAS) in UPJ-chil- RAS. Indeed, application of fluid shear stress on proximal
dren that can be linked to the observed increase in renin cells results in relocation of AT1-R out of apical recycling
activity (Table 6) (Decramer et al. 2007). proSAAS can inhi- endosomes into the apical surface membrane (Kolb et al.
bit prohormone convertase-1 (PC1) activity (Basak et al. 2004). Thus, tubular mechanical forces can account for
2001) and PC1 was shown to efficiently convert prorenin modifications of the RAS status in the obstructed kidney.
into renin (Benjannet et al. 1992). We therefore speculate In adults, blocking the RAS is a well-admitted target to
that the decline of proSAAS levels in UPJ-obstruction lower block the progression of renal diseases. AngII is involved in
PC1 inhibition and thus increase processing of renin from many, if not all, pathological mechanisms of renal fibrosis.
prorenin leading to increased activation of the RAS. Another It participates in the inflammatory process by stimulating
interesting finding is the effect of UUO on connexins 37 and expression of adhesion molecules such as VCAM-1 and
40 expression. Connexins 37 and 40 are two GAP junction ICAM-1, expression of chemokines such as CCL2 and
proteins, which are expressed in the renin-secreting cells of CCL5 (Mezzano et al. 2001; Ruster & Wolf 2006; Wynn
the juxtaglomerular apparatus and control in part the tubu- 2008). It is involved in oxidative stress by stimulating
lo-glomerular feedback (Takenaka et al. 2008; Just et al. NADPH oxidase activity and the production of reactive oxy-
2009). Intra-renal infusion of blocking peptides for Connex- gen species (Mezzano et al. 2001; Ruster & Wolf 2006;
in 37 and 40 increased plasma renin activity and AngII lev- Wynn 2008). It is also involved in EMT and fibroblast acti-
els (Takenaka et al. 2008). On the another hand, it has been vation (Mezzano et al. 2001; Ruster & Wolf 2006; Wynn
shown that mRNA expression of connexin 37 and 40 is 2008). Finally, AngII has been shown to induce collagen
increased during obstruction in neonatal rats (Table 6) (Sil- synthesis and TIMP-1 expression (Mezzano et al. 2001;
verstein et al. 2003b). Taken together, these results seem Ruster & Wolf 2006; Wynn 2008). Most of the effects of
controversial although one can speculate that the increased AngII are mediated by the modulation of cytokine and
renin expression during UUO can induce a positive feedback growth factor expression such as TGFa (Transforming
on connexin expression to limit the hyperreninemia. Growth Factor-a) and TGFb (Mezzano et al. 2001; Ruster
One major difference between animal models and human & Wolf 2006; Wynn 2008). It is interesting to point out
findings is the effect of obstruction on angiotensin receptors that most of these mechanisms and molecules are also
(Table 6). In rats with neonatal UUO, renal expression of induced in the neonatal model of UUO. However, targeting
type 1 and type 2 angiotensin receptors (AT1-R and AT2-R the RAS in infants is no longer considered to be a valuable
respectively) was decreased after 1 day of obstruction. How- therapeutic strategy. Blocking the RAS during renal develop-
ever after 4 weeks AT1-R was overexpressed whereas AT2- ment in human or rodents induces severe damage to the
R was still down-regulated (Yoo et al. 1997). In human, kidney and worsens the renal lesions induced by obstruction.
renal angiotensin receptor expression is not modified by Administration of angiotensin converting enzyme (ACE)
severe UPJ obstruction (Murer et al. 2006; Valles et al. inhibitors or AT1-R antagonists to pregnant women lead to
2007). Nevertheless, caveolin-1, which is colocalized with severe renal malformations in the foetus (Sekine et al. 2009).
the AT1-R in renal tubular cells, was induced in UPJ Moreover, a polymorphism into AT2-R gene involved in
obstruction both in renal biopsies and urine (Table 6) efficient splicing of the mRNA has been shown to be associ-
(Valles et al. 2007) suggesting that, although expression is ated with UPJ in two human cohorts (Nishimura et al.
not modified, AT1-R activation is increased. Altogether, 1999). In mouse, AT1-R, AT2-R and angiotensinogen gene
these data are in favour of activation of the RAS in UPJ knockout led to renal malformations (Sekine et al. 2009). In
obstruction. piglets with partial UUO, AT1-R blockade by candesartan
In vitro data show that renal RAS is activated by mechan- prevents interstitial and glomerular apoptosis but neither
ical stretch. This has been shown for podocytes or proximal fibrosis nor tubular dysfunction (Eskild-Jensen et al.
tubule cells where AngII production, renin mRNA and AT1- 2007a,b). In rats, losartan, another AT1-R antagonist,
R, but not AT2-R, expression are increased in response to aggravates lesions of partial UUO when administered during
stretch (Table 6) (Ricardo et al. 2000; Durvasula et al. the first 10 days of life, which corresponds to the period of
2004; Miceli et al. 2010). In addition, part of the stretch- nephrogenesis. However, losartan was without effect when
184 J. Klein et al.
administered 10 days after birth, which corresponds to the inflamed contralateral kidney and on renal development and
renal maturation period (Coleman et al. 2007). Inhibition of thus be potentially beneficial in obstructive nephropathy.
AT2-R was without effect at any time (Coleman et al. Further studies need to investigate whether this therapeutic
2007). Other studies have shown that enalapril, an ACE strategy is a valuable approach during congenital obstructive
inhibitor, induced functional and histological renal altera- nephropathy.
tions when administered during nephrogenesis (Guron et al.
1999), but did not exert additional deleterious effect in par-
Tubular transport and glomerular podocytes
tial UUO (Chen et al. 2007). Conversely, administration
during the maturation period had no effect in control rats As described above, UUO induces severe impairment of
(Guron et al. 1999) but worsened renal lesions induced by kidney function including profound modification of glomeru-
partial UUO (Chen et al. 2007). These results seem contro- lar filtration and tubular function. Little information about
versial. However it is important to keep in mind that ACE the regulation of renal transporters by mechanical stimuli is
inhibition or AT1-R blockade is not equivalent. ACE activ- available. Nevertheless, it appears that NHE and ENac, the
ity not only generates AngII but also other AngII related apical sodium transporters in proximal tubule and collecting
peptides such as Ang1-7, which exerts its biological effect duct respectively, are activated by fluid flow (Table 1) (Prei-
through AT1-R independent mechanisms (Ruster & Wolf sig 1992; Satlin et al. 2001). If the changes result from
2006). Moreover AngII can be generated by other serine hydrostatic pressure, membrane stretch or shear stress are
proteases than ACE, such as chymase, which is not affected however conflicting (Satlin et al. 2001; Carattino et al.
by ACE inhibition (Ruster & Wolf 2006). 2004). Besides, fluid flow augments apical and basal release
In conclusion, the RAS is induced during obstruction and of nucleotides which subsequently activates purinergic recep-
seems to be related to most of the deleterious mechanisms tors in isolated perfused renal tubules (Jensen et al. 2007).
involved in this pathology. However, the role of RAS during This effect is also observed in polarized MDCK cells sub-
kidney development is also crucial and cannot be targeted jected to transepithelial pressure changes (Praetorius et al.
easily. One alternative could be to target the RAS-associated 2005). Altogether, these results suggest that mechanical
kinin-kallikrein system (KKS). KKS is composed by two aggression could modify salt and water reabsorption in the
receptors, the B1 and the B2 receptors and by their respec- obstructed kidney (Sipos et al. 2009).
tive ligands, des-arg9bradykinin and bradykinin (Leeb-Lund- To our knowledge, the effect of UUO on the function of
berg et al. 2005). KKS is linked to the RAS through the glomerular podocytes has never been investigated in vivo,
ACE since ACE is not only involved into the conversion of neither in human nor in animals. However, numerous
AngI in AngII but also in the degradation of bradykinin stretching experiments have been performed in vitro using
(Leeb-Lundberg et al. 2005). podocytes. Indeed, these cells are probably subjected to
The B2 receptor has been shown to exert a renal protec- stretch in vivo during obstruction. First, when elevated
tive anti-fibrotic effect in different adult rodents models by hydrostatic pelvis pressure due to urine accumulation is
promoting extracellular matrix degradation (Schanstra et al. transmitted to Bowmans capsule, it could generate podocyte
2002; Okada et al. 2004; Seccia et al. 2006) and its expres- deformation. Moreover, when hydrostatic pressure increases
sion was increased during UUO in rat neonates (Table 6) in the glomerular capillary, as a result of afferent arteriole
(Chen et al. 2007). One can thus speculate that exogenous vasodilatation, it induces capillary distention, which may be
administration of B2 receptor ligand during neonatal transmitted to podocytes, leading to their stretching. As
obstructive nephropathy can be an interesting therapeutic mentioned above, stretched-podocytes show activation of
strategy. However the protective effects of ACE inhibitors in RAS and TGFb axis, stimulation of apoptosis and inhibition
adults are known to be mediated, at least in part, by of cellular proliferation. In addition to these effects, stretch
increased bradykinin expression or B2 receptor activation induces morphologic alterations such as podocyte hypertro-
(Okada et al. 2004; Seccia et al. 2006). Therefore the severe phy (Petermann et al. 2005) and stress fibers reorganization
renal alterations in rodents and humans during the neonatal (Endlich et al. 2001). It down-regulates a3b1 integrin
or the foetal period upon ACE inhibition might also be, at (Table 1), which allows podocyte ancrage to glomerular
least partially, mediated by bradykinin or its B2 receptor. basement membrane in vivo, thus leading to reduced cellular
On the another hand, we have recently demonstrated that adhesion (Dessapt et al. 2009). Finally, stretch reduces
kinin B1 receptor blockade significantly improves both renal expression of nephrin in podocyte foot process (Table 1), a
inflammation and fibrosis in two models of renal disease key protein of the slit diaphragm, thereby undermining the
(Klein et al. 2009, 2010). Contrarily to the B2 receptor, integrity of the filtration barrier. This effect is dependent of
which is constitutively expressed, the B1 receptor is not angiotensin-AT1-R system (Miceli et al. 2010) and could be
detectable under physiological conditions but over-expressed mediated by nephrin internalization. Indeed it was recently
at the site of injury during inflammation (Leeb-Lundberg demonstrated that nephrin trafficking depends on dynamin
et al. 2005). Moreover, B1 receptor knockout mice showed (Qin et al. 2009), a protein which is up-regulated in the
no renal alterations (Pesquero et al. 2000). All these argu- obstructed kidney after neonatal complete UUO (Silverstein
ments support the hypothesis that targeting the B1 receptor et al. 2003a). Altogether, these results suggest that stretch
during UUO in neonates should have limited impact on non- injury may induce podocyte dysfunction, thus leading to
proteinuria and ultimately glomerulosclerosis, as observed in
Table 7 Literature data about cytokine and growth factor-related genes and proteins that have been altered during obstructive nephropathy. We have reported here only mole-
Diamond et al. (1998),

Endlich et al. (2002)
adult rats having undergone UUO during nephogenesis (Che-
valier et al. 2000b). To test this hypothesis, further studies
et al. (2009)
on podocyte function and in particular on nephrin status
(Broadbelt
should be undertaken in human biopsies and animal models
cules of which activity or expression has been significantly modified compared to healthy control (human), sham-animals (animal model) or control cells (in vitro)
of UPJ obstruction.
Ref.
Other cytokines and growth factors
Pressure
Epidermal growth factor family. Members of the epidermal
Up*
growth factor (EGF) family are suggested to be mediators of
normal tubulogenesis and tubular regeneration (Zeng et al.
In vitro
Stretch
2009). In children studies on the urinary EGF secretion dur-
Up
ing UPJ obstruction have been contradictory. UPJ obstruc-
tion was found without effect on urinary EGF excretion
(Yang et al. 2006) while others have observed reduced uri-
Fenghua et al. (2009)

Nguyen et al. (1999a)
Nguyen et al. (1999a)

nary EGF expression (Grandaliano et al. 2000). However
Burt et al. (2007),

Chevalier (1996)
additional evidence on renal biopsies tends to support the
u: urine; t: tissue; p: plasma; w: weeks of obstruction; d: days of obstruction; CUUO: complete UUO; *activity; Ref.: references.
decreased renal EGF expression (Table 7) (Grandaliano
Chung and
et al. 2000; Yang et al. 2006).
Results in animal models are also complicated. In neona-
Ref.
tal rat subjected to complete UUO, a marked suppression of
EGF is observed in the obstructed kidney (Chung & Cheva-
lier 1996) whereas TGFa (Transforming Growth Factor-a),
(2w, 4w)
(2w, 4w)
to 4w)
to 4w)
CUUO
Up (5d
Up (5d
another ligand of the EGF family, and the EGF-receptor
Down
Down
Erb1 are up-regulated (Nguyen et al. 1999a). Moreover, in
rat neonatal partial UUO, although up-regulation of the
Animal model
TGFa and the EGF receptor was still observed, no signifi-
Up Down
(2w, 4w)
cant effect was shown in EGF and heparin-binding EGF
PUUO
(HB-EGF, a ligand for EGF-receptor) expression, after

24 weeks of obstruction (Table 7) (Bor et al. 2006).
Both EGF and TGFa are known to be involved in kidney
Taha et al. (2007a)
Yang et al. (2006),
Taha et al. (2007a)

development and alteration in their expression can thus be
associated with modified nephrogenesis or renal maturation
et al. (2000),
Grandaliano
(Carev et al. 2008; Zeng et al. 2009). But many in vivo and
in vitro observations indicate that EGF is mainly involved in
modulation of apoptosis during obstructive nephropathy.
Ref.
Interestingly, EGF can be a protector or a deleterious factor

depending on the disease severity and the species. Indeed,
= Down
EGF administration attenuates UUO-induced renal injury by

Human
(u, t)
Up (u)
increasing tubular proliferation and reducing apoptosis,

tubular dilation, tubular atrophy and interstitial fibrosis in
rat neonates (Chevalier et al. 1998; Wen et al. 2009). More-
over, while expression of EGF is not normalized after release
TGFa; transforming growth
of UUO (Chevalier et al. 1999a), EGF treatment improves

Epidermal growth factor
Epidermal growth factor
Osteopontin; secreted
recovery following relief (Chevalier et al. 1999a,c). In paral-

Vascular endothelial
phosphoprotein 1
lel, treatment with EGF decreases stretch-induced apoptosis

growth factor A
receptor; Erbb1
in rat proximal tubular cell in vitro (Nguyen et al. 2000;

Endothelin 1
Kiley et al. 2003). Conversely, EGF administration during

Gene name
factor a
neonatal mouse obstruction does not correct UUO-induced

apoptosis in vivo (Kiley et al. 2005) and aggravates stretch-
induced apoptosis in mouse proximal tubular cell in vitro
(Kiley et al. 2005). In addition, obstructed kidney of neona-
Gene symbol
tal mice lacking EGF or with diminished EGF receptor activ-

ity elicit less apoptosis than wild-type mice (Kiley et al.
Vegfa
2005). It was proposed that constitutive Src activity in

Edn1
Spp1
Tgfa
Egfr
Egf
mouse is the underlying cause of EGF receptor dysregulation
186 J. Klein et al.
and susceptibility to EGF-induced cell death (Kiley & suggest that IGF-1 may be a potential therapeutic target in
Chevalier 2007). the pathology of obstructive nephropathy.
Because of these striking species differences, it is hard
to speculate whether EGF administration could be benifi- Endothelin-1. Endothelin-1 (ET-1) is a potent vasoconstric-
cial or deleterious in humans. However it is interesting to tor that has been implicated in the tissue damage and dys-
point out that application of elevated pressure activates function associated with UUO (Josephson & Hemsen 1994;
the EGF receptor in human proximal tubular cells in vitro Feldman et al. 2000) and UPJ obstruction (Taha et al.
(Table 7) and consecutively leads to iNOS and NO 2007a). It has been shown that urinary ET-1 levels were
expression which has been shown to attenuate experimen- 4-fold higher in UPJ obstruction patients than in healthy
tal obstructive renal injury (see above) (Broadbelt et al. controls, patients with vesicoureteral reflux and patients
2009). with renal stones (Table 7). Surgery decreased urinary ET-1
levels that slowly declined over 1 year (Taha et al. 2007a).
Vascular endothelial growth factor. Vascular endothelial This shows that, as observed for urinary TGFb, that relief of
growth factor (VEGF) is a pleiotropic cytokine known to be obstruction does not rapidly decrease the concentrations of
involved in many processes in kidney physiology and pathol- molecules that are potentially involved in disease progres-
ogy such as glomerular capillary development and perme- sion.
ability regulation (Robert & Abrahamson 2001; Schrijvers
et al. 2004), growth and proliferation of glomerular and Osteopontin. Osteopontin is a secreted glycosylated phos-
peritubular capillary endothelial cells (Schrijvers et al. 2004) phoprotein, which has been shown to be up-regulated in a
or inhibition of apoptosis in tubular epithelial cells (Villegas number of experimental models of renal disease and in
et al. 2005). It has been often proposed that during renal human nephropathy (Xie et al. 2001). Osteopontin seems
diseases increased VEGF levels can prevent the loss of peri- to have two opposite roles in the kidney. On one hand,
tubular capillaries, thus reducing hypoxia and subsequent osteopontin has been shown to promote macrophage che-
development of renal fibrosis. However, a number of studies motaxis and renal fibrosis (Xie et al. 2001; Tian et al.
have shown that VEGF can be either deleterious or benefi- 2006). On another hand, osteopontin is strongly involved
cial, depending on the form of renal disease (Schrijvers et al. in renal protection by inhibiting oxidative stress, decreasing
2004). In neonates, relationships between experimental interstitial and tubular cell apoptosis and participating in
UUO and VEGF are not fully understood. While complete the regeneration of tubular cells (Xie et al. 2001). Many
UUO induced a complete loss of renal VEGF expression in factors have been shown to be involved in increased osteo-
foetal lambs and neonatal rats (Burt et al. 2007; Fenghua pontin expression, such as TNF-a, PDGF, TGFb and EGF
et al. 2009), partial UUO in neonatal rats led to strong and it has been shown that osteopontin could modulate
inter-individual heterogeneity, with VEGF expression AngII-induced renal injury (Xie et al. 2001; Wolak
varying between down- to up-regulation (Table 7) (Burt et al.2009). Following mechanical stretch, rat proximal
et al. 2007). Moreover, exogenous VEGF administration cells and mouse podocytes exhibit an increase in osteopon-
tended to aggravate the UUO-induced loss of peritubular tin mRNA levels, which is normalized following pretreat-
capillaries (Burt et al. 2007). All these results suggest a com- ment with an AT1-R antagonist (Table 7) (Diamond et al.
plex role of VEGF on the developing kidney during obstruc- 1998; Endlich et al. 2002). Experimental UUO in osteo-
tive nephropathy, depending on the severity of the disease pontin knockout neonatal mice showed that osteopontin
and probably on the global pathological context. blockade exerted a deleterious role on tubular and intersti-
tial apoptosis (Yoo et al. 2006b). However this result was
Insulin-like growth factor. Different studies have shown that counterbalanced by an attenuation of fibrotic lesions in
insulin-like growth factor 1 (IGF-1) could play a protective osteopontin knockout compared to WT mice, although no
role in the pathology of obstructive nephropathy. As stated significant effect was shown on macrophage accumulation
above, mechanical stretch of proximal cells induced Bad- (Yoo et al. 2006b). In this study, the effect of osteopontin
mediated cell death in vitro (Kiley et al. 2003). Interestingly, blockade on functional parameters has not been investi-
treatment with IGF-1 during stretch strongly decreased gated. Future experiments should explore whether the pro-
apoptosis by restoring bad phosphorylation level (Kiley tective (i.e. anti-apoptotic) or deleterious (i.e. pro-fibrotic)
et al. 2003). Altough IGF-1 and IGF-1 receptors expression role of osteopontin dominates on kidney function during
is not modified during neonatal UUO in rats exogenous IGF- obstructive nephropathy.
1 administration significantly decreased the UUO-induced
apoptosis as well as tubular atrophy and interstitial fibrosis
Renal development
(Chevalier et al. 2000a). Similarly, while increasing inflam-
mation, IGF-1 administration protected against the loss of Finally, as stated previously, the major difference between
renal architecture and decreased interstitial fibrosis during adult and neonatal UUO models is the impairment of imma-
UUO in opossum pups (Steinhardt et al. 1995). Studies mea- ture kidney development. Very interestingly, some studies
suring the effect of IGF-1 administration on UUO-induced have shown that UUO induced up-regulation of some genes
loss of renal function are absent. However these results involved in kidney embryogenesis, such as decorin and lumi-
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Int. J. Exp. Path.

(2011), 92, 168192

Congenital ureteropelvic junction obstruction: human disease and

obstruction is efficient in protecting against short term

Histological lesions Functional modifications

Tubulo-glomerular disconnection Decreased Na+ reabsorption

Figure 1 Histological lesions and functional modifications induced by obstruction.

Animal model In vitro

AQP1 Aquaporin 1 Down (24w) Shi et al. (2004a)

significant apoptotic lesions was still observed (Chevalier

Elevated tubular pressure

Animal model In vitro

Ager RAGE; receptor for Up (1d) Lange-Sperandio

Animal model In vitro

flow stimulates NO release and induces eNOS activation

Miyajima et al. (2000a),

Broadbelt et al. (2007)

Ricardo et al. (1997)

pressure or shear stress modifications, experiments have been

(Broadbelt et al. 2007) or stretch (Miyajima et al. 2000b;

effect of stretch seems to be species-dependent as the NO

increase is induced in rat but not in human cells (Miyajima

inhibition whereas NO inhibitors amplify them. These

collecting duct cells (Cai et al. 2000). This latter result is

more difficult to directly transpose to the in vivo UUO situa-

ever it suggests that tubular NO production could be also

sensitive to urinary shear stress variations.

Another consequence of chronic UUO in newborns is the

increases superoxide production and down-regulates catalase

Hong 2008). In vivo, 2 weeks of complete UUO in neonatal

rats induced NADPH oxidase activity and decreased super-

oxide dismutase activity (Table 4) (Manucha & Valles

proliferation of renal cells, such as mesangial cells, podo-

angiotensin II (Ang II) (Jiang 2009). Consistently with these

results up-regulation of NADPH oxidase activity paralleled

ing the deleterious role of oxidative stress during neonatal

Apoptosis and proliferation

During obstruction, tubular stretch, inflammation and oxida-

tive stress induce a severe apoptotic response of both tubular

and interstitial cells. Indeed urinary tubular enzymes poten-

tially released by those cells including N-acetyl-b-d-glucosa-

role of other intracellular mediators of apoptosis or cell sur-

In rats, mice and opossums complete and partial UUO stim-

ulated expression and activity of pro-apoptotic molecules

Animal model In vitro

Alpl Alkaline phosphatase Up* (u) Shokeir and

Animal model In vitro

proteinuria and ultimately glomerulosclerosis, as observed in

Diamond et al. (1998),

Fenghua et al. (2009)

Nguyen et al. (1999a)

Burt et al. (2007),

TGFa and the EGF receptor was still observed, no signifi-

(HB-EGF, a ligand for EGF-receptor) expression, after

Taha et al. (2007a)

Interestingly, EGF can be a protector or a deleterious factor

EGF administration attenuates UUO-induced renal injury by

increasing tubular proliferation and reducing apoptosis,

of UUO (Chevalier et al. 1999a), EGF treatment improves

Epidermal growth factor

recovery following relief (Chevalier et al. 1999a,c). In paral-

lel, treatment with EGF decreases stretch-induced apoptosis

in rat proximal tubular cell in vitro (Nguyen et al. 2000;

Kiley et al. 2003). Conversely, EGF administration during